High score review: the impact of 7 types of hypoglycemic drugs on "muscle"

Yimaitong compiles and organizes, please do not reprint without authorization
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Introduction: To reduce the risk of sarcopenia in diabetic patients, how to optimize the use of 7 types of hypoglycemic drugs? Recently, a review published in the Journal of cachexia, sarcopenia and muscle (IF: 12.
91) summarized and analyzed the latest research progress of major anti-diabetic drugs regulating muscle mass/function, and discussed “to reduce the risk of sarcopenia "The best choice for the purpose of anti-diabetic drugs
.

Vicious cycle-sarcopenia, diabetes and poor blood sugar control.
Skeletal sarcopenia is a muscle wasting syndrome characterized by progressive and systemic degenerative loss of skeletal muscle mass (SMM), mass and strength, often Accompanied by aging and many chronic diseases appear
.

In addition to muscle wasting, patients with sarcopenia are at higher risk of falls, fractures, and metabolic diseases, leading to a significant reduction in the quality of life
.

 Diabetic patients have a higher incidence of sarcopenia (the risk is about twice that of ordinary people)
.

Moreover, because skeletal muscle, as the largest tissue of the human body, plays a very important role in energy and metabolic homeostasis, the loss of muscle mass and function will have a negative impact on blood sugar control and form a vicious circle with metabolic disorders (Figure 1)
.

Improving muscle mass and reducing the risk of muscle loss are of particular importance to the clinical care of diabetic patients
.

Note: Green, generally protective; black, controversial; red: generally causing damage.
Figure 1 The effect of hypoglycemic drugs on the muscle mass/performance of patients.
The effect of 7 categories of hypoglycemic drugs on muscles.
Current evidence shows that there are different categories.
The blood sugar lowering drugs have different effects on muscle mass/function (Figure 1, Table 1)
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 Table 1 Effects of 7 types of hypoglycemic drugs on muscles (current evidence) Note: FBFM, fat and bone-free mass; FFM, non-fat mass; FM, fat mass; GS, grip strength ; SMI: skeletal muscle index; SMM, skeletal muscle mass 1.
Insulin Insulin is generally considered to be protective for muscles
.

In addition to regulating blood sugar, insulin is also a powerful stimulator of muscle protein synthesis
.

However, considering the patients' own insulin resistance, endothelial dysfunction and diabetic microangiopathy, the positive effect of insulin on the muscle mass of T2DM patients may be "discounted
.
"
A previous study of Japanese patients showed that insulin therapy can reduce the decline in muscle strength of the lower limbs (but not the decline in muscle strength of the upper limbs)
.

A recent longitudinal study of insulin therapy and changes in muscle parameters showed that insulin can preserve muscle mass, but it does not seem to have an effect on muscle function (as assessed by grip strength)
.

It is worth noting that some early clinical studies involving insulin therapy and body composition have shown that insulin-induced weight gain is mainly due to the increase in fat and fat-free mass (FFM)
.

Especially typical in T2DM patients, weight gain mainly reflects the increase in main FM
.

Therefore, the effect of insulin therapy on bone mass may vary depending on the type of diabetes, and whether the central obesity of T2DM partially offsets the other benefits of insulin therapy remains to be determined
.

 2.
Sulfonylureas and Glinides Sulfonylureas and Glinides are generally believed to cause damage to muscles
.

Sulfonylureas and Glinide drugs stimulate insulin secretion by inhibiting the ATP-sensitive K+ (KATP) channel, which has a hypoglycemic effect
.

Preclinical data indicate that KATP channel blockers are related to muscle atrophy
.

In addition, studies have found that glibenclamide can enhance the activity of caspase-3 in the slow body and reduce the ratio of protein concentration to muscle weight
.

In view of the close relationship between KATP channels and skeletal muscle homeostasis, the inhibitory effects of sulfonylureas and glinides on KATP channels increase the possibility that these drugs may have adverse effects on SMM and function
.

A previous database search study investigated atrophy-related signals related to the use of sulfonylureas and glinides
.

The results showed that within 8 months, 0.
27% of patients with glibenclamide were reported to have muscle atrophy, which was 12 times the total reported incidence of other drugs
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It is suggested that the drug-induced atrophy may be related to the blockade of KATP channel and the enhancement of mitochondrial succinate dehydrogenase activity
.

It is suggested that glibenclamide and other drugs should be used with caution in patients with a high tendency to decrease skeletal muscle
.

 3.
Metformin Metformin is generally considered to be controversial for muscles
.

Metformin can improve insulin resistance and hyperinsulinemia through a variety of mechanisms.
Its metabolic benefits are attributed to its effects on multiple tissues, usually including liver, intestine, adipose tissue and muscle.
The most important mechanism is the activation of AMPK signaling pathway.

.

Weight loss is usually accompanied by metformin treatment, and many studies have agreed that long-term use of metformin is associated with a decrease in FM
.

However, the effect of metformin on the lean body mass of patients with T2DM is still controversial
.

Musi et al.
confirmed that there was no significant change in FFM after 10 weeks of metformin treatment
.

Similar results were found in a 6-month clinical study of 29 newly diagnosed T2DM patients
.

In contrast, a multicenter longitudinal cohort study recruiting ambulatory men over 65 years of age showed that compared with untreated diabetic patients or non-metformin-treated diabetic patients, the total lean mass of men treated with metformin or The loss of lean body mass in the limbs was significantly reduced
.

The authors speculate that this effect may be caused by the up-regulation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) by AMPK
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Consistent with this, it has been reported that in non-diabetic subjects, taking metformin for 2 months can increase lean body mass and water content
.

Overall, although the effects of these findings on body composition are inconsistent, the effects of bone quality and performance need to be considered when designing metformin-based diabetes treatments
.

Considering that metformin may cause appetite suppression and intestinal oligopeptide absorption, the risk of muscle loss should be considered in clinical metformin treatment, especially in women with T2DM and elderly patients
.

 4.
Thiazolidinedione TZDS is generally considered to be controversial for muscle
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Thiazolidinediones (TZDs) drugs enhance insulin sensitivity in muscle, liver, and adipose tissue by activating peroxisome proliferation-activated receptor γ (PPAR-γ)
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Preclinical studies have shown that TZDs, as insulin sensitizers, may play an active role in maintaining SMM and its functions
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In particular, studies on skeletal muscle cells have shown that rosiglitazone reduces apoptosis through a PPAR-γ-dependent mechanism
.

It has also been reported that rosiglitazone can effectively inhibit the transcription of nuclear factor kappa B (NF-κB) induced by inflammatory mediators, which can reduce protein degradation in the myotubes of cultured skeletal muscle
.

An early multicenter longitudinal study by Lee et al.
reported that TZD can reduce the loss of muscle mass in patients with impaired fasting blood glucose or diabetes
.

However, the ACT NOW trial showed that after 33.
6 months of pioglitazone treatment, the lean body mass of the legs of patients with prediabetes decreased significantly, and the weight increased significantly, while the overall lean body mass did not change
.

Early case reports showed that some patients with T2DM developed acute rhabdomyolysis after receiving pioglitazone or troglitazone treatment
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Therefore, when encountering patients with skeletal muscle diseases, prescribing TZD needs to be cautious
.

 5.
GLP-1RA GLP-1RA is generally considered to be protective for muscles
.

Glucagon-like peptide-1 (GLP-1) is a natural incretin hormone secreted by intestinal L cells, which can enhance the secretion of glucose-dependent insulin, restore the glucose sensitivity of pancreatic β-cells, and inhibit hyperglycemia Prime release
.

Pernaet et al.
evaluated the role of liraglutide in overweight/obese elderly patients with T2DM
.

After receiving liraglutide for 24 weeks, researchers found that the weight loss was mainly due to the decrease in FM, and liraglutide could prevent the degradation of muscle protein and maintain the stability of skeletal muscle
.

However, in another study involving 21 patients with T2DM on hemodialysis, the addition of dulaglutide to insulin therapy can significantly reduce FM and SMM, suggesting that the drug has a risk of muscle reduction
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A recent meta-analysis of randomized controlled trials also showed that semaglutide is associated with weight loss and FFM reduction, which prompted us to understand the effect of drug specificity on sarcopenia parameters
.

 6.
DPP-4i DPP-4i is generally considered to be protective for muscles
.

Dipeptidyl peptidase IV inhibitors (DPP-4i) such as sitagliptin, vildagliptin and saxagliptin can increase endogenous GLP-1 to achieve the hypoglycemic effect
.

Although DPP-4i does not increase the weight of patients with T2DM, studies have found that it has the potential to improve skeletal muscle damage
.

As mentioned above, dyskinesias in diabetic patients mainly occur in the lower limbs, especially the quadriceps
.

Bouchiet confirmed the protective effect of DPP-4i on muscle dysfunction in patients with T2DM in a retrospective study, especially the protective effect of lower extremity muscles
.

In a clinical study of 80 elderly patients with T2DM, compared with sulfonylurea treatment, DPP-4i (vildagliptin 50mg bid or sitagliptin 100mg/day or saxagliptin 5mg/day) showed Develop better muscle reduction parameters (FFM, SMM, muscle strength and gait speed)
.

These clinical benefits are supported by animal studies
.

For example, Bianchiet et al.
demonstrated that PKF275-055 (an analog of vildagliptin) can partially ameliorate streptozotocin-induced white fiber muscle damage in type 1 diabetic rats
.

Enokiet et al.
found that teneliliptin has the potential to treat muscle dysfunction in mice with chronic kidney disease (CKD), suggesting that teneliliptin can not only play a cytoprotective effect indirectly through GLP-1, but also directly act on CKD-induced muscle atrophy
.

In addition, Giannoccoet et al.
found that sitagliptin can up-regulate the displacement and expression of GLUT4 in the myocardium and skeletal muscle of spontaneously hypertensive rats
.

Interestingly, the FDA warned that high doses of DPP-4i can cause acute toxicity in monkeys, including an increase in creatine kinase (CK) activity (pathological increases in CK activity are common in muscular dystrophy)
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However, the researchers also pointed out that the acute toxicity caused by vildagliptin seems to only exist in monkeys, and it is currently uncertain whether it will occur in humans
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Therefore, the effect of DPP-4i on skeletal muscle in clinical application needs further research
.

 7.
SGLT-2i SGLT-2i is generally considered to be controversial for muscles
.

Sodium-glucose cotransporter 2 inhibitor (SGLT-2i) selectively inhibits SGLT2, reduces the reabsorption of glucose in the proximal tubule, increases urinary glucose excretion, and reduces blood glucose concentration
.

Representative drugs currently in use include dapagliflozin, canagliflozin, enpagliflozin and so on
.

SGLT2i is effective in inducing weight loss, and about 90% of weight loss is due to the reduction of FM
.

Other studies have also shown that the use of SGLT2i in T2DM patients can reduce two-thirds of FM and one-third of lean body mass
.

However, a randomized controlled trial found that after 24 weeks of treatment, dapagliflozin significantly reduced subcutaneous and visceral fat, but had no effect on lean tissue
.

Sasaki et al.
found that the SMM of T2DM patients treated with luseogliflozin did not change significantly after 36 weeks of treatment, while the bone mineral content (BMC) decreased only briefly after 12 weeks of treatment, and then remained unchanged
.

Consistent with the results of these clinical studies, when diet-induced obesity (DIO) rats were treated with tofogliflozin, there was no significant change in bone mass and lean body mass
.

Interestingly, Naznine et al.
found that treatment with canagliflozin for 8 weeks can cause weight loss in mice, which is characterized by a decrease in visceral and subcutaneous fat mass
.

Despite these findings, there are still concerns that SGLT2i may cause loss of muscle and bone mass, osteoporosis, and decreased body function
.

 To reduce the risk of muscle loss, pay attention to the rational use of hypoglycemic drugs.
In summary: ➤Metformin, TZD and SGLT2i: The effect of metformin, TZD and SGLT2i on muscle is still controversial, and more individualized clinical studies are needed
.

➤Sulfonylureas and Glinides: Almost all studies have proved that sulfonylureas and Glinides have adverse effects on skeletal muscle, suggesting that diabetic patients with skeletal sarcopenia need to avoid these drugs
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➤GLP-1RA and DPP-4i: GLP-1RA and DPP-4i may be beneficial to muscle protection, not only reducing the loss of muscle mass, but also promoting muscle contraction and improving muscle damage
.

➤Insulin: Although studies have shown that insulin can increase the muscle mass of patients with T2DM, the weight gain effect of insulin cannot be ignored and should be carefully considered in the treatment of patients with T2DM
.

 Yimaitong compiled and compiled from: Zhang X, Zhao Y, Chen S, et al.
Anti-diabetic drugs and sarcopenia: emerging links, mechanistic insights, and clinical implications[J].
J Cachexia Sarcopenia Muscle,2021.